To Investigate the Therapeutic Efforts of the COX-2 Inhibitor NS-398 as a Single Agent, and in Combination with Vitamin D, in Vitro and in Vivo

摘要

With disease progression, the majority of the prostate cancers would eventually evolve into lethal aggressive hormone refractory disease; therefore, there are needs for developing new strategies to prevent the disease progression. We have identified a cross-talk between vitamin D and COX-2 inhibitor, two chemopreventative agents for prostate cancer, and conducted series investigations of their anti-prostate cancer effects with the funding support from DOD, which have led to generation of three publications. First, we identified the molecular mechanism by which vitamin D inhibits prostate cancer angiogenesis through IL-8, finding a strong correlation of IL-8 expression with prostate cancer disease progression, therefore, inhibition of IL-8 by vitamin D supports the chemotherapeutic effects of vitamin D in preventing prostate cancer progression. Second, we studied the vitamin D-based combination with docetaxel therapy. Docetaxel is the only treatment shown to improve overall survival in hormonal refractory prostate cancer patients (HRPC); however the survival benefit is modest. Treatment with docetaxel in combination with the active form of vitamin D has shown promising results in prostate specific antigen (PSA) response, time to progression and survival in HRPC patients. Our detailed mechanism of this combination therapy was studied to provide a further therapeutic design. Third, the mechanism(s) of elevation of COX-2 expression in late stage of disease and its contribution to the cancer progression were further explored. We found that androgen/AR signals suppressed COX-2 activity, therefore the blockage of androgen signals in complete androgen blockage therapy would then consequently result in elevated COX-2 expression and promote the disease progression. The clinical use of COX-2 inhibitors has recently become controversial due to cardiovascular complications associated with the use of COX-2 inhibitor for prolonged periods of time.